LGR4, LGR5, and LGR6 comprise a group of proteins in the leucine-rich repeat-containing G-protein-coupled receptors (LGR). They are known to play important and non-redundant roles in development, stem cells, and cancer. These functions are generally independent of heterotrimeric G proteins or ?-arrestin and have been attributed to their role in potentiating Wnt signaling. However, we have discovered that LGR4 can also bind and sequester CBL, a known E3 ligase for pEGFR, independent of RSPO. And we also found that LGR4 can regulate the level of phosphorylated EGFR independent of RSPO and Wnt signaling. Therefore, our preliminary data suggest a provocative new signaling pathway by which these LGR proteins regulate human cancer. Furthermore, we found that LGR4 is most highly expressed in BLBC compared to the other breast cancer subtypes, and that its knockdown in BLBC breast cancer cell lines inhibits cell migration and invasion in vitro and metastases in vivo. Therefore, these preliminary data suggest the hypothesis that LGR4 binds CBL and prevents it from targeting pEGFR for ubiquitin-mediated proteasomal degradation, leading to sustained EGFR signaling, and that this novel LGR4-CBL-EGFR signaling pathway, together with LGR4-stimulated Wnt signaling, promotes BLBC invasion and metastasis. Consequently, blockade of both EGFR and canonical Wnt signaling could prevent or treat metastasis of BLBC, which often has elevated levels of LGR4. To test this hypothesis and its potential clinical implications, we propose three aims: Aim 1: To elucidate the novel interaction between LGR4 and CBL in relation to EGFR activation. Aim 2: To establish LGR4 roles in breast cancer metastasis using mouse models and patient-derived xenografts (PDXs). Aim 3: To determine in mouse models, PDX, and human clinical samples whether both EGFR and Wnt signaling play critical roles in breast cancer metastasis stimulated by LGR4, and whether blockade of both EGFR and canonical Wnt signaling prevents and treats metastases of BLBC more effectively than blockade of either one alone.